For a given light dose, the cytotoxic efficacy of pleural photodynamic therapy (pPDT) is modulated by two interrelated cancer cell properties: 1) the intrinsic sensitivity to pPDT-mediated cytotoxicity and 2) intracellular photosensitizer (PS) levels. Despite unprecedented survival with radical pleurectomy (RP)/pPDT for patients with malignant pleural mesothelioma (MPM), local relapses remain a significant source of treatment failure and patients who experience early (<12mo) local relapse exhibit an aggressive and rapidly fatal clinical course. These data suggest optimization of PDT strategies by improving patient selection and developing methods to overcome cancer cell resistance to PDT would be clinically valuable. In the previous funding period, we demonstrated that activation of inflammatory signaling through signal transducer and activator of transcription (STAT3) and cyclooxygenase 2 (COX-2) decreases PDT-mediated, direct cancer cell cytotoxicity both increasing intrinsic cancer cell resistance to apoptotic cell death and decreasing cellular levels of specific photosensitizers. In preliminary data, we have found that surgically-induced cytokines activate STAT3 and are associated with decreased PDT efficacy (clinical/preclinical studies) and that Celecoxib, an inhibitor of Cox-2, enhances cancer cell PS levels and reduces the detrimental effects of surgery on PDT (preclinical studies). Finally, inhibiting STAT3 expression the effect of Celecoxib on PS level, accentuating the potential importance of STAT3 as a potential point of integration between inflammatory signaling and inhibition of direct PDT cytotoxicity. These data lead us to hypothesize that STAT3 pathway activation is a significant contributor to the local relapse following RP/pPDT and that modulating this pathway will improve clinical results. The Specific Aims of this application involve the molecular mechanisms by which activation of STAT3 and interrelated signaling pathways, such as COX-2, modulate pPDT efficacy. Aim 1 will determine whether baseline or surgically-induced STAT3 and Cox-2 pathway activation decreases pPDT efficacy in maintaining local (pleural) control of MPM following RP/pPDT using samples from patients. Aim 2 will determine the mechanisms by which surgically-induced activation of STAT3 and Cox-2 signaling pathways alter PDT efficacy and whether modulation of these pathways will decrease the negative impact of surgical resection on the efficacy of PDT for MPM using a combination of in vitro and in vivo MPM models. By sharing clinical samples and pre-clinical models with Projects 2 and 4, a greater understanding of the relative value of improving pPDT-mediated local control will emerge and inform the design of future clinical trials. Moreover, by identifying mechanisms by which surgery negatively impacts PDT efficacy and developing clinically applicable methods to surmount this challenge, this project will help to remove a critical barrier to the more widespread application of resection with intraoperative PDT as a treatment paradigm in other cancers with high rates of local relapse following surgery.